Changing the Scientific Landscape: The Discovery of Stem Cells
By: Melissa Galati
Dr. Alan Bernstein, President and Chief Executive Officer (CEO) of the Canadian Institute For Advanced Research (CIFAR), once wrote in a Globe and Mail article, “If Canada’s game is hockey, it’s science is stem cells” (1). When we think of Canadian contributions to medical research, we’re quick to recall the discovery of insulin for the treatment of diabetes by Drs. Frederick Banting and Charles Best. It seems a shame, however, that so few Canadians recognize that stem cells were discovered in their own backyard. In fact, Canada has a storied history of contributions to stem cell research, the implications of which hold immense promise for the treatment of a myriad of conditions and diseases including spinal cord injuries, blindness, cancer, Parkinson’s Disease, and many others. This history begins in 1961 with a discovery by two University of Toronto (U of T) scientists, Dr. Ernest Armstrong “Bun” McCulloch—co-founder of the Institute of Medical Science (IMS)—and his colleague Dr. James Edgar Till.
Dr. McCulloch, who was born and raised in Toronto, attended U of T for his undergraduate studies. Despite his penchant for humanities—he was editor of his high school’s magazine and studied English literature throughout his undergraduate education—he decided to pursue medicine, believing that this would allow him to govern his own career. “I learned enough about myself to settle on a career in medicine: I did not like discipline—therefore I wanted to work for myself—to be my own boss” (2).
After graduating from medical school at U of T in 1948, Dr. McCulloch spent the following year training at the Lister Institute in London, where he was exposed to clinical research—in particular, studies of the immune system. Upon his return to Toronto, Dr. McCulloch spent the next decade specializing in haematology and slowly taking on a greater role in teaching and research. In fact, by the time Dr. McCulloch received his appointment to the newly formed Ontario Cancer Institute (OCI—now the Princess Margaret Cancer Centre) in 1957, he had almost completely transitioned out of the clinic and on to the laboratory bench.
At the OCI, Dr. McCulloch set out to cure leukemia. He received funding to study the effects of radiation on mammalian cells, a project that was of particular interest to the public in light of the Cold War. The task, however, would require the knowledge of a fellow OCI scientist. Dr. Till, a Canadian physicist who had studied radiation physics during his PhD at Yale University, had enjoyed Dr. McCulloch’s presentations at some of the more informal meetings they attended and offered his expertise as Dr. McCulloch set out to conduct these seminal experiments. Perhaps unbeknownst to them, their partnership would last the duration of their scientific careers.
Although the existence of stem cells was already suspected and postulated, Dr. McCulloch and Dr. Till were the first to find and quantify them. Their now famous experiments involved injecting both healthy mouse bone marrow cells—which we now know include hematopoietic stem cells (HSCs)—and irradiated mouse bone marrow cells into mice that had been given a lethal dose of radiation. Although they had originally sought to determine the effects of radiation on normal cells compared to cancer cells, their results showed that the survival of the irradiated animals depended on the number of live bone marrow cells injected. The more cells injected, the better the survival of the mice. They also discovered tiny nodules on the surface of the spleens of mice injected with normal bone marrow cells. The number of nodules, which Dr. McCulloch and Dr. Till very cautiously termed “colony forming units” (CFUs), was directly proportional to the number of cells injected (3). As you might guess, these spleen CFUs were full of proliferating cells and were able to generate red blood cells, white blood cells, and platelets—the three main components of blood! We now know that Dr. McCulloch and Dr. Till had observed the two defining features of stem cells: that they could both give rise to all the different blood cells in the body, as well as “self-renew” (create more of themselves).
Their results, although exciting at the time, did not receive much attention until nearly 30 years later. Even their trainees, many of whom would later become giants in their respective fields, could not have predicted the weight of those initial findings. Dr. Connie Eaves, current Director of the Terry Fox Laboratory BC Cancer Agency recalls, “I don’t think I knew that they were making history in the way that we understand now” (4). At the time, the stem cell field did not attract the attention and excitement it does today. Another trainee, Dr. Norman Iscove—now Senior Scientist at the OCI—comments, “Till and McCulloch created a landscape for scientific investigation where none had existed prior to their arrival” (4).
Many of the PhD candidates that passed through Dr. McCulloch’s laboratory also possessed Medical Doctorate (MD) degrees. Because these students were thought to have formal training in biological sciences, they were prevented from taking biology related courses in graduate school. This rule grew to frustrate Dr. McCulloch, who taught the graduate courses in biology and knew that his course material would not have been taught in medical school. At the same time, Dr. John (Jack) Coleman Laidlaw, an endocrinologist at Toronto General Hospital, became similarly dissatisfied with the research training received by MD graduate students. This training, which typically took the form of a year-long apprenticeship, often lacked proper evaluation. As a result, it was unclear whether students were taught proper research methodology. A more structured training regime was needed, but one that was not quite as rigid as those basic science departments already existing in U of T’s School of Graduate Studies (SGS). The IMS was conceptualized in response to this need, achieving official approval in September of 1968.
Dr. McCulloch, who was the first IMS Graduate Secretary—now termed Graduate Coordinator—and its second director (succeeding Dr. Laidlaw), was essential to the department’s formative years. It seems fitting that McCulloch’s career had and would continue to embody the central tenets of the IMS. His partnership with Dr. Till—the marrying of biological and physical sciences—was a multidisciplinary team conducting groundbreaking translational research before the term was even coined. It is hard to imagine that Dr. Laidlaw and Dr. McCulloch faced so much scrutiny in the early years of the IMS—now the largest department in the Faculty of Medicine with greater than 600 faculty and 500 students.
Dr. McCulloch passed away at the age of 84 on January 20, 2011, 50 years after his initial discoveries were first published. He and Dr. Till are two of Canada’s most decorated scientists, receiving nearly every major honour and award including both the Gairdner Foundation International Award in 1969 and the Albert Lasker Award in 2005. They were both named Officers of the Order of Canada and inducted into the Canadian Medical Hall of Fame. Moreover, their research became the foundation for future breakthroughs in the stem cell field, many of which were achieved by Canadian scientists. For his contributions to research, his scientific integrity, and for his fostering of the next generation of Canadian scientists, we in the IMS are proud to call Dr. McCulloch one of our founding fathers.
1. Bernstein A. If Canada’s game is hockey, its science is stem cells. The Globe and Mail [serial online]. 2012 Mar 7 [cited 2018 Jan 3]. Available from: https://www.theglobeandmail.com/opinion/if-canadas-game-is-hockey-its-science-is-stem-cells/article551653/
2. Science.ca. Ernest McCulloch, Cell Biologist [Internet]. c2013 [last updated 2013 Oct 28; cited 2018 Jan 3]. Available from: http://www.science.ca/scientists/scientistprofile.php?pID=468&-lang=en
3. Stem Cell Foundation. Till & McCulloch’s Stem Cell Legacy [Internet]. 2012 [cited 5 January 2018]. Available from: https://www.youtube.com/watch?time_continue=1&v=iVunbUSFgWs
4. CMak TW. Ernest Armstrong McCulloch. 21 April 1926—20 January 2011. Biogr Mems Fell R Soc [serial online]. 2017 [cited 2018 Jan 3] DOI: 10.1098/rsbm.2017.0019. Available from: http://rsbm.royalsocietypublishing.org/content/roybiogmem/early/2017/11/19/rsbm.2017.0019